Pharmaceutical aqueous formulation comprising 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea

ABSTRACT

The present invention relates to a pharmaceutical aqueous formulation comprising 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea, or a pharmaceutically acceptable alkanesulphonate salt thereof, that is a clear solution. Such a formulation is particularly suitable for intravenous or parenteral administration to a patient.

CROSS-REFERENCE TO RELATED APPLICATIONS

This Application is the national stage filing under 35 U.S.C. 371 ofPatent Cooperation Treaty Patent Application No. PCT/IB2018/056281,filed Aug. 20, 2018, which claims the benefit of priority from U.S.Provisional Application No. 62/550,007 filed Aug. 25, 2017, U.S.Provisional Application No. 62/681,720 filed Jun. 7, 2018 and U.S.Provisional Application No. 62/703,022 filed Jul. 25, 2018, the contentsof each of which are hereby incorporated by reference in their entirety.

The present invention relates to a pharmaceutical formulation comprising1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea,or a pharmaceutically acceptable alkanesulphonate salt thereof. Morespecifically, the present invention relates to a pharmaceutical aqueousformulation comprising1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea,or a pharmaceutically acceptable alkanesulphonate salt thereof, that isa clear solution. Such a formulation is particularly suitable forintravenous or parenteral administration to a patient.

1-(4-{[4-(Dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea,and preparations thereof, are disclosed in WO2009/143313. The compoundis an inhibitor of PI3 kinase and mTOR that is useful for the treatmentof cancer.

A crystalline form of1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea,and process for the preparation thereof, are disclosed in WO2010/096619.

WO2016/097949 describes a pharmaceutical aqueous solution formulationsuitable for intravenous administration comprising (i)1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea,or a lactate salt thereof, lactic acid and water, wherein1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]ureais present at a solution concentration of less than 6 mg/ml andsufficient lactic acid is present to provide a clear solution; or (ii)1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea,or a phosphate salt thereof, orthophosphoric acid and water, wherein1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]ureais present at a solution concentration of less than 4 mg/ml andsufficient orthophosphoric acid is present to provide a clear solution.Lyophilisation of such formulations are also described. Of the manyacids tested (i.e. citric acid, succinic acid, acetic acid, glycine,tartaric acid, maleic acid, malic acid, hydrochloric acid, lactic acidand orthophosphoric acid), only lactic acid and orthophosphoric acid arefound to be capable of achieving a clear solution with a concentrationof1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]ureaof 3 mg/ml or above.

1-(4-{[4-(Dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea,also known as gedatolisib, has the chemical structure:

1-(4-{[4-(Dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]ureamay be prepared in crystalline form and is chemically and physicallystable at 25° C. and 60% Relative Humidity (RH) for up to 3 years inthis form. However, this free base is insufficiently water soluble toallow the preparation of an aqueous solution formulation suitable forintravenous or parenteral administration at the therapeutic dosagelevels required.

There is a need to develop a pharmaceutically acceptable aqueoussolution formulation of1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]ureathat is (a) chemically stable on storage (e.g. at 25° C. and 60% RH),(b) that will facilitate effective intravenous (or parenteral)administration of the drug to a mammal, including a human being, and(c), preferably, to achieve a solution concentration of1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]ureathat is at least 6 mg/ml.

A solution concentration of1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]ureathat is at least 6 mg/ml is desirable to allow dose administration tosubjects using a single vial presentation of the commercial drugproduct. A lyophilised drug product (for reconstitution) containing lessthan 6 mg/ml drug product solution will require multiple vials todeliver the required therapeutic dose. A multiple vial approach to dosedelivery is not desirable given current regulatory expectations forthese product types.

Preferably, the formulation is suitable for intravenous or parenteraladministration of1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]ureain view of the particular pharmacokinetic and bioavailabilitycharacteristics of this drug.

It is essential that an intravenous formulation of any drug is asolution to facilitate safe and effective administration to a patient.It must be particle-free, and not form a gel or suspension. A clear,aqueous solution is preferred.

A “clear solution” is defined herein as a visually clear solution, whichmay bear a solution opalescence, that is essentially free from anyvisible particulates that can be observed on a visual inspection.Generally, if any particulate matter is observed, the formulation is notsuitable for intravenous administration and should not be utilised asocclusion of blood vessels may occur. Accordingly, in view of thequalitative nature of the visual test, the term “essentially free fromany visible particulates” is usually applied when no visible particulatematter is observed.

Particulate matter may be defined as follows:

-   -   speck—discrete particle whose shape cannot be determined without        magnification    -   smoke or swirl—fine particles that look like smoke or a tornado        and usually originate from the sample vial floor and twist        upward as the vial is swirled    -   flocculent material—loosely aggregated particles or soft flakes    -   particulates with a definite shape or characteristic can be        described as glass-like, metallic-looking, etc.

The visual inspection can be conducted in accordance with the methoddefined in European Pharmacopoeia Method 2.9.20 entitled “Particulatecontamination: visible particles”. This method determines particulatecontamination of injections and infusions by extraneous, mobile,undissolved particles, other than gas bubbles, that may be present inthe solutions. The test is intended to provide a simple procedure forthe visual assessment of the quality of parenteral solutions as regardsvisible particles.

In European Pharmacopoeia Method 2.9.20 the apparatus (see “FIG. 2.9.20.-i” shown in FIG. 3 ) consists of a viewing station comprising:

-   -   a matt black panel of appropriate size held in a vertical        position    -   a non-glare white panel of appropriate size held in a vertical        position next to the black panel    -   an adjustable lampholder fitted with a suitable, shaded,        white-light source and with a suitable light diffuser (a viewing        illuminator containing two 13 Watt fluorescent tubes, each 525        mm in length, is suitable). The intensity of illumination at the        viewing point is maintained between 2000 lux and 3750 lux,        although higher values are preferable for coloured glass and        plastic containers.

The Method states: “Remove any adherent labels from the container andwash and dry the outside. Gently swirl or invert the container, ensuringthat air bubbles are not introduced, and observe for about 5 seconds infront of the white panel. Repeat the procedure in front of the blackpanel. Record the presence of any particles.” A suitable method inaccordance with European Pharmacopoeia Method 2.9.20 that has been usedfor the present invention is described in Example 1(i).

Other validated methods may be also be used for the dermination of ifany visible particulates are present. Such methods include OpticalPolarised Microscopy (“OPM”). A suitable OPM method that has been usedfor the present invention is described in Example 1(ii).

The present invention relates to a pharmaceutical aqueous formulationcomprising1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea,or a methanesulphonate or ethanesulphonate salt thereof,methanesulphonic acid or ethanesulphonic acid, and, optionally, apharmaceutically acceptable beta- or gamma-cyclodextrin, that is a clearsolution (hereafter “the formulation of the invention”).

Preferably, methanesulphonic acid (and methanesulphonate salts) are usedin the formulations of the invention.

In an embodiment of the invention is provided a pharmaceutical aqueoussolution formulation comprising (a)1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea,or a methanesulphonate salt thereof, methanesulphonic acid and water,wherein1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]ureais present at a solution concentration of less than 35 mg/ml or up to 30mg/ml and sufficient methanesulphonic acid is present to provide a clearsolution; or (b)1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea,or an ethanesulphonate salt thereof, ethanesulphonic acid and water,wherein1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]ureais present at a solution concentration of less than 35 mg/ml or up to 30mg/ml and sufficient ethanesulphonic acid is present to provide a clearsolution.

In an embodiment of the invention is provided a pharmaceutical aqueoussolution formulation comprising (a)1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea,or a methanesulphonate salt thereof, methanesulphonic acid and water,wherein1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]ureais present at a solution concentration of from 6 to 30 mg/ml andsufficient methanesulphonic acid is present to provide a clear solution;or (b)1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea,or an ethanesulphonate salt thereof, ethanesulphonic acid and water,wherein1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]ureais present at a solution concentration of from 6 to 30 mg/ml andsufficient ethanesulphonic acid is present to provide a clear solution.

The “solution concentration” values referred to herein relate to theconcentration of the free base of1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]ureain the formulation of the invention.

It has been found that the use of methanesulphonic acid andethanesulphonic acid enables a solution concentration of up to 30 mg/mlof1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]ureato be achieved for a pharmaceutical aqueous solution formulation that issuitable for intravenous or parenteral administration to a patient, i.e.a clear, essentially particle-free solution. Such formulations may havean opalescent hue but they are still essentially particle-free.

Without being bound by theory, the opalescent hue may be caused bychromonic liquid crystal formation. Chromonic liquid crystals are formedby the formation of pi-pi stacked aromatic sections of a moleculeforming column like stacks of dimers, trimers and low molecular weightoligomers of the molecules. The stacks that form can be shown via OPM tobe non-crystalline microstructures associated to a chromonic liquidcrystal. The non-crystalline microstructures exhibit interactions thatare not permanent and there is movement to maintain the system in a freeenergy equilibrium. The opalescence of the solution comes from thealteration of the refractive index of the solution due to the formationof these stacks. OPM micrographs of the solutions will show that thereis no crystalline material present and instead there is a chromonicliquid crystal phase. The presence of a liquid crystal phase results ina solution with opacity and/or opalescence due to a difference inrefractive index within the solution formed. For a discussion on liquidcrystal formation see “Optical Properties of Condensed Matter andApplications”, Jai Singh (Editor), ISBN: 978-0-470-02193-4, Wiley,October 2006.

Such a formulation can be directly administered to the patient (in orderto avoid degradation occurring), intravenously or parenterally,preferably with the addition of a tonicity modifier. Alternatively, foradministration to a patient at a later date, such a formulation,optionally containing a bulking agent and/or tonicity modifier, may befirst freeze-dried to prepare a lyophilised solid composition that ischemically stable on storage for preferably at least 2 years, and whichlyophilised solid composition then can be constituted, or reconstituted,to provide a clear aqueous solution, preferably with the addition of atonicity modifier, as necessary, immediately prior to administration toa patient by the intravenous (or parenteral) route. The reconstituted orconstituted solution may be added to an infusion bag prior toadministration to a patient.

In respect of the formulations comprising methanesulphonic acid, it hasbeen found that above a solution concentration of1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]ureaof 35 mg/ml or above, the necessary clear solutions at the pH requiredfor intravenous administration to a patient are not obtained, or are notobtained consistently.

In respect of the formulations comprising ethanesulphonic acid, it hasbeen found that above a solution concentration of1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]ureaof above 35 mg/ml or above, the necessary clear solutions at the pHrequired for intravenous administration to a patient are not obtained,or are not obtained consistently.

One embodiment of the formulation of the invention provides apharmaceutical aqueous solution formulation comprising1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea,methanesulphonic acid and water, wherein1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]ureais present at a solution concentration of less than 35 mg/ml or up to 30mg/ml and sufficient methanesulphonic acid is present to provide a clearsolution.

One embodiment of the formulation of the invention provides apharmaceutical aqueous solution formulation comprising1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]ureamethanesulphonate, methanesulphonic acid and water, wherein1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]ureais present at a solution concentration of less than 35 mg/ml or up to 30mg/ml and sufficient methanesulphonic acid is present to provide a clearsolution.

One embodiment of the formulation of the invention provides apharmaceutical aqueous solution formulation comprising1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea,methanesulphonic acid and water, wherein1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]ureais present at a solution concentration of from 6 to 30 mg/ml andsufficient methanesulphonic acid is present to provide a clear solution.

One embodiment of the formulation of the invention provides apharmaceutical aqueous solution formulation comprising1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]ureamethanesulphonate, methanesulphonic acid and water, wherein1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]ureais present at a solution concentration of from 6 to 30 mg/ml andsufficient methanesulphonic acid is present to provide a clear solution.

One embodiment of the formulation of the invention provides apharmaceutical aqueous solution formulation comprising1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea,methanesulphonic acid and water, wherein1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]ureais present at a solution concentration of from 6 to 22 mg/ml andsufficient methanesulphonic acid is present to provide a clear solution.

One embodiment of the formulation of the invention provides apharmaceutical aqueous solution formulation comprising1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]ureamethanesulphonate, methanesulphonic acid and water, wherein1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]ureais present at a solution concentration of from 6 to 22 mg/ml andsufficient methanesulphonic acid is present to provide a clear solution.

One embodiment of the formulation of the invention provides apharmaceutical aqueous solution formulation comprising1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea,methanesulphonic acid and water, wherein1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]ureais present at a solution concentration of from 8 to 30 mg/ml, from 10 to30 mg/ml, from 8 to 22 mg/ml, from 10 to 22 mg/ml, from 15 to 22 mg/ml,from 6 to 25 mg/ml or from 10 to 25 mg/ml, and sufficientmethanesulphonic acid is present to provide a clear solution.

One embodiment of the formulation of the invention provides apharmaceutical aqueous solution formulation comprising1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]ureamethanesulphonate, methanesulphonic acid and water, wherein1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]ureais present at a solution concentration of from 8 to 30 mg/ml, from 10 to30 mg/ml, from 8 to 22 mg/ml, from 10 to 22 mg/ml, from 15 to 22 mg/ml,from 6 to 25 mg/ml or from 10 to 25 mg/ml, and sufficientmethanesulphonic acid is present to provide a clear solution.

One embodiment of the formulation of the invention provides apharmaceutical aqueous solution formulation comprising1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea,ethanesulphonic acid and water, wherein1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]ureais present at a solution concentration of less than 35 mg/ml or up to 30mg/ml and sufficient ethanesulphonic acid is present to provide a clearsolution.

One embodiment of the formulation of the invention provides apharmaceutical aqueous solution formulation comprising1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]ureaethanesulphonate, ethanesulphonic acid and water, wherein1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]ureais present at a solution concentration of less than 35 mg/ml or up to 30mg/ml and sufficient ethanesulphonic acid is present to provide a clearsolution.

One embodiment of the formulation of the invention provides apharmaceutical aqueous solution formulation comprising1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea,ethanesulphonic acid and water, wherein1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]ureais present at a solution concentration of from 6 to 30 mg/ml andsufficient ethanesulphonic acid is present to provide a clear solution.

One embodiment of the formulation of the invention provides apharmaceutical aqueous solution formulation comprising1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]ureaethanesulphonate, ethanesulphonic acid and water, wherein1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]ureais present at a solution concentration of from 6 to 30 mg/ml andsufficient ethanesulphonic acid is present to provide a clear solution.

One embodiment of the formulation of the invention provides apharmaceutical aqueous solution formulation comprising1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea,ethanesulphonic acid and water, wherein1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]ureais present at a solution concentration of from 6 to 22 mg/ml andsufficient ethanesulphonic acid is present to provide a clear solution.

One embodiment of the formulation of the invention provides apharmaceutical aqueous solution formulation comprising1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]ureaethanesulphonate, ethanesulphonic acid and water, wherein1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]ureais present at a solution concentration of from 6 to 22 mg/ml andsufficient ethanesulphonic acid is present to provide a clear solution.

One embodiment of the formulation of the invention provides apharmaceutical aqueous solution formulation comprising1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea,ethanesulphonic acid and water, wherein1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]ureais present at a solution concentration of from 8 to 30 mg/ml, from 10 to30 mg/ml, from 8 to 22 mg/ml, from 10 to 22 mg/ml, from 15 to 22 mg/ml,from 6 to 25 mg/ml or from 10 to 25 mg/ml, and sufficientethanesulphonic acid is present to provide a clear solution.

One embodiment of the formulation of the invention provides apharmaceutical aqueous solution formulation comprising1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]ureaethanesulphonate, ethanesulphonic acid and water, wherein1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]ureais present at a solution concentration of from 8 to 30 mg/ml, from 10 to30 mg/ml, from 8 to 22 mg/ml, from 10 to 22 mg/ml, from 15 to 22 mg/ml,from 6 to 25 mg/ml or from 10 to 25 mg/ml, and sufficientethanesulphonic acid is present to provide a clear solution.

A further embodiment of the formulation of the invention may optionallyadditionally comprise a pharmaceutically acceptable beta- orgamma-cyclodextrin. Examples of such a pharmaceutically acceptablebeta-cyclodextrin are 2-hydroxypropyl-beta-cyclodextrin andsulphobutylether-3-cyclodextrin (SBECD). Examples of such apharmaceutically acceptable gamma-cyclodextrin are gamma-cyclodextrinand 2-hydroxypropyl-gamma-cyclodextrin. Preferably,hydroxypropyl-beta-cyclodextrin is used in the formulations of theinvention. By use of a pharmaceutically acceptable beta- orgamma-cyclodextrin it has been found that clear solutions may beachieved with no opalescence and/or containing higher concentrations of1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea.

One embodiment of the formulation of the invention provides apharmaceutical aqueous solution formulation comprising1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea,methanesulphonic acid, 2-hydroxypropyl-beta-cyclodextrin and water,wherein1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]ureais present at a solution concentration of less than 55 mg/ml or up to 50mg/ml and sufficient methanesulphonic acid and2-hydroxypropyl-beta-cyclodextrin are present to provide a clearsolution.

One embodiment of the formulation of the invention provides apharmaceutical aqueous solution formulation comprising1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]ureamethanesulphonate, methanesulphonic acid,2-hydroxypropyl-beta-cyclodextrin and water, wherein1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]ureais present at a solution concentration of less than 55 mg/ml or up to 50mg/ml and sufficient methanesulphonic acid and2-hydroxypropyl-beta-cyclodextrin are present to provide a clearsolution.

One embodiment of the formulation of the invention provides apharmaceutical aqueous solution formulation comprising1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea,methanesulphonic acid, 2-hydroxypropyl-beta-cyclodextrin and water,wherein1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]ureais present at a solution concentration of up to 45 mg/ml, up to 40mg/ml, up to 35 mg/ml, up to 30 mg/ml, from 6 to 50 mg/ml, from 6 to 30mg/ml, from 8 to 30 mg/ml, from 10 to 35 mg/ml, from 10 to 30 mg/ml,from 8 to 22 mg/ml, from 10 to 22 mg/ml, from 15 to 22 mg/ml, from 10 to20 mg/ml, from 6 to 25 mg/ml or from 10 to 25 mg/ml and sufficientmethanesulphonic acid and 2-hydroxypropyl-beta-cyclodextrin are presentto provide a clear solution.

One embodiment of the formulation of the invention provides apharmaceutical aqueous solution formulation comprising1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]ureamethanesulphonate, methanesulphonic acid,2-hydroxypropyl-beta-cyclodextrin and water, wherein1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]ureais present at a solution concentration of up to 45 mg/ml, up to 40mg/ml, up to 35 mg/ml, up to 30 mg/ml, from 6 to 50 mg/ml, from 6 to 30mg/ml, from 8 to 30 mg/ml, from 10 to 35 mg/ml, from 10 to 30 mg/ml,from 8 to 22 mg/ml, from 10 to 22 mg/ml, from 15 to 22 mg/ml, from 10 to20 mg/ml, from 6 to 25 mg/ml or from 10 to 25 mg/ml and sufficientmethanesulphonic acid and 2-hydroxypropyl-beta-cyclodextrin are presentto provide a clear solution.

One embodiment of the formulation of the invention provides apharmaceutical aqueous solution formulation comprising1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea,methanesulphonic acid, sulphobutylether-3-cyclodextrin and water,wherein1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]ureais present at a solution concentration of less than 35 mg/ml or up to 30mg/ml and sufficient methanesulphonic acid andsulphobutylether-β-cyclodextrin are present to provide a clear solution.

One embodiment of the formulation of the invention provides apharmaceutical aqueous solution formulation comprising1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]ureamethanesulphonate, methanesulphonic acid,sulphobutylether-3-cyclodextrin and water, wherein1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]ureais present at a solution concentration of less than 35 mg/ml or up to 30mg/ml and sufficient methanesulphonic acid andsulphobutylether-3-cyclodextrin are present to provide a clear solution.

One embodiment of the formulation of the invention provides apharmaceutical aqueous solution formulation comprising1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea,methanesulphonic acid, sulphobutylether-3-cyclodextrin and water,wherein1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]ureais present at a solution concentration of from 6 to 30 mg/ml, from 8 to30 mg/ml, from 10 to 30 mg/ml, from 8 to 22 mg/ml, from 10 to 22 mg/ml,from 15 to 22 mg/ml, from 10 to 20 mg/ml, from 6 to 25 mg/ml or from 10to 25 mg/ml and sufficient methanesulphonic acid andsulphobutylether-3-cyclodextrin are present to provide a clear solution.

One embodiment of the formulation of the invention provides apharmaceutical aqueous solution formulation comprising1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]ureamethanesulphonate, methanesulphonic acid,sulphobutylether-3-cyclodextrin and water, wherein1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]ureais present at a solution concentration of from 6 to 30 mg/ml, from 8 to30 mg/ml, from 10 to 30 mg/ml, from 8 to 22 mg/ml, from 10 to 22 mg/ml,from 15 to 22 mg/ml, from 10 to 20 mg/ml, from 6 to 25 mg/ml or from 10to 25 mg/ml and sufficient methanesulphonic acid andsulphobutylether-β-cyclodextrin are present to provide a clear solution.

One embodiment of the formulation of the invention provides apharmaceutical aqueous solution formulation comprising1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea,methanesulphonic acid, gamma-cyclodextrin and water, wherein1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]ureais present at a solution concentration of less than 35 mg/ml or up to 30mg/ml and sufficient methanesulphonic acid and gamma-cyclodextrin arepresent to provide a clear solution.

One embodiment of the formulation of the invention provides apharmaceutical aqueous solution formulation comprising1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]ureamethanesulphonate, methanesulphonic acid, gamma-cyclodextrin and water,wherein1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]ureais present at a solution concentration of less than 35 mg/ml or up to 30mg/ml and sufficient methanesulphonic acid and gamma-cyclodextrin arepresent to provide a clear solution.

One embodiment of the formulation of the invention provides apharmaceutical aqueous solution formulation comprising1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea,methanesulphonic acid, gamma-cyclodextrin and water, wherein1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]ureais present at a solution concentration of from from 6 to 30 mg/ml, from8 to 30 mg/ml, from 10 to 30 mg/ml, from 8 to 22 mg/ml, from 10 to 22mg/ml, from 15 to 22 mg/ml, from 10 to 20 mg/ml, from 6 to 25 mg/ml orfrom 10 to 25 mg/ml and sufficient methanesulphonic acid andgamma-cyclodextrin are present to provide a clear solution.

One embodiment of the formulation of the invention provides apharmaceutical aqueous solution formulation comprising1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]ureamethanesulphonate, methanesulphonic acid, gamma-cyclodextrin and water,wherein1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]ureais present at a solution concentration of from 6 to 30 mg/ml, from 8 to30 mg/ml, from 10 to 30 mg/ml, from 8 to 22 mg/ml, from 10 to 22 mg/ml,from 15 to 22 mg/ml, from 10 to 20 mg/ml, from 6 to 25 mg/ml or from 10to 25 mg/ml and sufficient methanesulphonic acid and gamma-cyclodextrinare present to provide a clear solution.

One embodiment of the formulation of the invention provides apharmaceutical aqueous solution formulation comprising1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea,ethanesulphonic acid, 2-hydroxypropyl-beta-cyclodextrin and water,wherein1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]ureais present at a solution concentration of less than 40 mg/ml or up to 35mg/ml and sufficient ethanesulphonic acid and2-hydroxypropyl-beta-cyclodextrin are present to provide a clearsolution.

One embodiment of the formulation of the invention provides apharmaceutical aqueous solution formulation comprising1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]ureaethanesulphonate, ethanesulphonic acid,2-hydroxypropyl-beta-cyclodextrin and water, wherein1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]ureais present at a solution concentration of less than 40 mg/ml or up to 35mg/ml and sufficient ethanesulphonic acid and2-hydroxypropyl-beta-cyclodextrin are present to provide a clearsolution.

One embodiment of the formulation of the invention provides apharmaceutical aqueous solution formulation comprising1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea,ethanesulphonic acid, 2-hydroxypropyl-beta-cyclodextrin and water,wherein1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]ureais present at a solution concentration of up to 30 mg/ml, from 6 to 30mg/ml, from 8 to 30 mg/ml, from 10 to 35 mg/ml, from 10 to 30 mg/ml,from 8 to 22 mg/ml, from 10 to 22 mg/ml, from 15 to 22 mg/ml, from 10 to20 mg/ml, from 6 to 25 mg/ml or from 10 to 25 mg/ml and sufficientethanesulphonic acid and 2-hydroxypropyl-beta-cyclodextrin are presentto provide a clear solution.

One embodiment of the formulation of the invention provides apharmaceutical aqueous solution formulation comprising1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]ureaethanesulphonate, ethanesulphonic acid,2-hydroxypropyl-beta-cyclodextrin and water, wherein1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]ureais present at a solution concentration of up to 30 mg/ml, from 6 to 30mg/ml, from 8 to 30 mg/ml, from 10 to 35 mg/ml, from 10 to 30 mg/ml,from 8 to 22 mg/ml, from 10 to 22 mg/ml, from 15 to 22 mg/ml, from 10 to20 mg/ml, from 6 to 25 mg/ml or from 10 to 25 mg/ml and sufficientethanesulphonic acid and 2-hydroxypropyl-beta-cyclodextrin are presentto provide a clear solution.

One embodiment of the formulation of the invention provides apharmaceutical aqueous solution formulation comprising1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea,ethanesulphonic acid, sulphobutylether-3-cyclodextrin and water, wherein1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]ureais present at a solution concentration of less than 40 mg/ml or up to 35mg/ml and sufficient ethanesulphonic acid andsulphobutylether-β-cyclodextrin are present to provide a clear solution.

One embodiment of the formulation of the invention provides apharmaceutical aqueous solution formulation comprising1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]ureaethanesulphonate, ethanesulphonic acid, sulphobutylether-3-cyclodextrinand water, wherein1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]ureais present at a solution concentration of less than 40 mg/ml or up to 35mg/ml and sufficient ethanesulphonic acid andsulphobutylether-3-cyclodextrin are present to provide a clear solution.

One embodiment of the formulation of the invention provides apharmaceutical aqueous solution formulation comprising1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea,ethanesulphonic acid, sulphobutylether-3-cyclodextrin and water, wherein1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]ureais present at a solution concentration of up to 30 mg/ml, from 6 to 30mg/ml, from 8 to 30 mg/ml, from 10 to 30 mg/ml, from 8 to 22 mg/ml, from10 to 22 mg/ml, from 15 to 22 mg/ml, from 10 to 20 mg/ml, from 6 to 25mg/ml or from 10 to 25 mg/ml and sufficient ethanesulphonic acid andsulphobutylether-3-cyclodextrin are present to provide a clear solution.

One embodiment of the formulation of the invention provides apharmaceutical aqueous solution formulation comprising1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]ureaethanesulphonate, ethanesulphonic acid, sulphobutylether-3-cyclodextrinand water, wherein1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]ureais present at a solution concentration of up to 30 mg/ml, from 6 to 30mg/ml, from 8 to 30 mg/ml, from 10 to 30 mg/ml, from 8 to 22 mg/ml, from10 to 22 mg/ml, from 15 to 22 mg/ml, from 10 to 20 mg/ml, from 6 to 25mg/ml or from 10 to 25 mg/ml and sufficient ethanesulphonic acid andsulphobutylether-β-cyclodextrin are present to provide a clear solution.

One embodiment of the formulation of the invention provides apharmaceutical aqueous solution formulation comprising1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea,ethanesulphonic acid, gamma-cyclodextrin and water, wherein1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]ureais present at a solution concentration of less than 25 mg/ml or up to 20mg/ml and sufficient ethanesulphonic acid and gamma-cyclodextrin arepresent to provide a clear solution.

One embodiment of the formulation of the invention provides apharmaceutical aqueous solution formulation comprising1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]ureaethanesulphonate, ethanesulphonic acid, gamma-cyclodextrin and water,wherein1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]ureais present at a solution concentration of less than 25 mg/ml or up to 20mg/ml and sufficient methanesulphonic acid and gamma-cyclodextrin arepresent to provide a clear solution.

One embodiment of the formulation of the invention provides apharmaceutical aqueous solution formulation comprising1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea,ethanesulphonic acid, gamma-cyclodextrin and water, wherein1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]ureais present at a solution concentration of from 6 to 20 mg/ml, from 8 to20 mg/ml, from 10 to 20 mg/ml, from 8 to 15 mg/ml, or from 15 to 20mg/ml and sufficient ethanesulphonic acid and gamma-cyclodextrin arepresent to provide a clear solution.

One embodiment of the formulation of the invention provides apharmaceutical aqueous solution formulation comprising1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]ureaethanesulphonate, ethanesulphonic acid, gamma-cyclodextrin and water,wherein1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]ureais present at a solution concentration of from 6 to 20 mg/ml, from 8 to20 mg/ml, from 10 to 20 mg/ml, from 8 to 15 mg/ml, or from 15 to 20mg/ml and sufficient ethanesulphonic acid and gamma-cyclodextrin arepresent to provide a clear solution.

The preferred concentration of methanesulphonic acid or ethanesulphonicacid for use in a formulation of the invention is from 10 to 200 mM, 20to 200 mM, 30 to 200 mM or from 50 to 200 mM, and preferably is about 50mM, about 100 mM or about 150 mM. Preferably, the concentration ofmethanesulphonic acid or ethanesulphonic acid is about 100 mM.Preferably, about a 100 mM concentration of methanesulphonic acid isused.

The preferred amount of pharmaceutically acceptable beta- orgamma-cyclodextrin for use in a formulation of the invention is from 2to 30% w/v, 3 to 20% w/v, from 5 to 20% w/v or from 15 to 30% w/v, andpreferably is about 20% w/v or 25% w/v. Preferably, the amount ofpharmaceutically acceptable beta- or gamma-cyclodextrin for use in aformulation of the invention is about 20% w/v.

If the formulation of the invention is to be freeze-dried to provide alyophilised solid composition, a bulking agent may be added to theformulation prior to the freeze-drying process commencing. A bulkingagent may not be present if the formulation of the invention contains apharmaceutically acceptable beta- or gamma-cyclodextrin. The primaryfunction of the bulking agent is to provide the freeze-dried solid witha non-collapsible, structural integrity that will allow rapidreconstitution on constitution of the aqueous formulation prior toadministration, and it should also facilitate efficient lyophilisation.Bulking agents are typically used when the total mass of solutes in theformulation is less than 2 g/100 ml. Bulking agents may also be added toachieve isotonicity with blood. The bulking agent may be selected from asaccharide, sugar alcohol, amino acid or polymer, or be a mixture of twoor more of any thereof. Preferably, the bulking agent is a sugar orsugar alcohol, or a mixture thereof. Preferably, the sugar is sucrose.Preferably, the sugar alcohol is mannitol.

Preferably, from 5 to 10% w/v of a bulking agent is used, if present.

Reconstitution of the lyophilised solid composition may be achieved byaddition of the requisite quantity of water that was present prior tolyophilisation in order that a clear solution is obtained. A tonicitymodifier may then be added prior to use.

Constitution of the lyophilised solid composition may be achieved usingan appropriate quantity of water and/or an aqueous solution of asuitable tonicity modifier in order to ensure that a clear solution isobtained.

A tonicity modifier may be present prior to intravenous or parenteraladministration of the formulation to a patient by injection to avoidcrenation or hemolysis of red blood cells, and to mitigate or avoid painand discomfort to the patient. This requires that the formulation to beadministered to the patient has an effective osmotic pressure that isapproximately the same as that of the blood of the patient.

Suitable tonicity modifiers are non-ionic tonicity modifiers such asglycerol, sorbitol, mannitol, sucrose, propylene glycol or dextrose, ora mixture of any 2 or more thereof. Preferably the non-ionic tonicitymodifier is dextrose, sucrose or mannitol, or is a mixture of any 2 ormore thereof.

Preferably, from 1 to 5% w/v of a tonicity modifier is used.

Aqueous pharmaceutical formulations of the invention that are suitablefor intravenous administration generally have a pH of from 3 to 9.However, lower pH values are tolerated in certain settings. Preferably,the pH is from 3 to 8 or from 4 to 8.

The formulation of the invention may be used for the curative,palliative or prophylactic treatment of cancer in a mammal, including ahuman being. The cancer to be treated may be selected from the groupconsisting of leukemia, skin cancer, bladder cancer, breast cancer,uterus cancer, ovary cancer, prostate cancer, lung cancer, colon cancer,pancreas cancer, renal cancer, gastric cancer and brain cancer.

The weekly dose of1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]ureato be administered by the intravenous route for the treatment of cancerusing the formulations disclosed herein is preferably in the range offrom 100 to 400 mg per week.

The following Figures illustrate the claimed invention:

FIG. 1 : OPM micrographs of Example 5B containing 22 mg/ml of1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]ureain 100 mM ESA

FIG. 2 : OPM micrographs of Example 5A containing 22 mg/ml of1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]ureain 100 mM MSA

FIG. 3 : re. European Pharmacopoeia Method 2.9.20: “FIG. 2.9.20.-1.—Apparatus for visible particles”

The following Examples describe the preparation of the formulations ofthe invention.

EXAMPLE 1 Preparation of a Pharmaceutical Aqueous Solution FormulationComprising 22 mg/ml of1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]ureaand methanesulfonic acid

Methanesulfonic acid (99% w/w purity) (0.65 ml) was dissolved in waterfor irrigation (80 ml).1-(4-{[4-(Dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea(220 mg) was added to the solution and stirred until a particle-freesolution was achieved. Water for irrigation was added with stirring toachieve a target volume of 100 ml.

(i) Visual Analysis

A sample of the formulation was analysed in accordance with the visualmethod defined in European Pharmacopoeia Method 2.9.20 (using a Verivide(trade mark) light cabinet and a light meter reading of 3250 lux againsta matt black panel and a white panel) to determine if crystallites orparticles were present. The sample was tested by this method both whenthe solution was first made up and then 24 hours thereafter.

(ii) OPM Analysis

A sample of the formulation was placed on a clean glass microscopy slideand covered with a glass cover slip. It was then analysed by OPM usingboth non-polarised and cross-polarised light under a Nikon LV 100POL(trade mark) microscope with a 10× magnification lens and a 10×magnification eyepiece to determine if crystallites or particles werepresent. The image was recorded using a DFK 23UP031 TIS USB 3.0 CMOS(trade mark) Colour Industrial Camera 5 MP 1/2,5″ and image capturesoftware. The procedure was also repeated using a sample of theformulation in a glass capillary tube. The sample was tested by thismethod when the solution was first made up, and then at 4 and 24 hoursthereafter.

EXAMPLE 2 Preparation of a Pharmaceutical Aqueous Solution FormulationComprising 22 mg/ml of1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]ureaand ethanesulfonic acid

Ethanesulfonic acid (70% w/v) (3144.7 microL), was diluted with waterfor irrigation (80 ml).1-(4-{[4-(Dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea(220 mg) was added to the solution and stirred until a particle-freesolution was achieved. Water for irrigation was added with stirring toachieve target volume of 100 ml.

Samples of the formulation were analysed in accordance with the methodsof Example 1.

EXAMPLE 3 Preparation of (a) a Pharmaceutical Aqueous SolutionFormulation Comprising 22 mg/ml of1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea,methanesulfonic acid and mannitol; and (b) a lyophilised compositionthereof

-   -   (a) Methanesulfonic acid (99% w/w purity) (0.65 ml) was        dissolved in water for irrigation (80 ml). Mannitol (2.8 g) was        dissolved in this buffer solution by stirring to achieve total        dissolution.        1-(4-{[4-(Dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea        (220 mg) was added to the solution and stirred until a        particle-free solution was achieved. Water for irrigation was        added with stirring to achieve a target volume of 100 ml.        -   Samples of the formulation were analysed in accordance with            the methods of Example 1.    -   (b) The formulation from (a) was filled into 10 mL vials to a        target volume of 3 ml. The vials were partially stoppered (not        sealed) with a 20 mm Gray Lyo D777-i V10-F597W FluroTec        Siliconised (trade mark) stopper. The vials were loaded into        stainless steel trays and inserted into a LSL1000 (trade mark)        freeze dryer. The shelf temperature was set at 5° C. The freeze        drying cycle was run using the tabulated method below.

Temper- Temperature ature change Rate/ (degrees Time (degrees C.)Condition Hold C.) (min.) per minute Pressure Loading Hold 5 n/a n/a 760Torr (1 Atmosphere) Stabilisation Hold 5 120 n/a 760 Torr (1 Atmosphere)Freeze Rate −40 480 0.1 deg. C./min 760 Torr (1 Atmosphere) Hold −40 180n/a 760 Torr (1 Atmosphere) Annealing Rate −12 280 0.1 deg. C./min 760Torr (1 Atmosphere) Hold −12 180 n/a 760 Torr (1 Atmosphere) CoolingRate −40 280 0.1 deg. C./min 760 Torr (1 Atmosphere) Evacuation Hold −40100 n/a 90 mTorr Primary Hold −40 30 n/a 90 mTorr Drying Rate −30 1000.5 deg. C./min 90 mTorr Hold −30 5450 n/a 90 mTorr Secondary Rate 20500 0.5 deg. C./min 90 mTorr Drying Hold 20 500 n/a 90 mTorr Rate 40 2000.5 deg. C./min 90 mTorr Hold 40 500 n/a 90 mTorr

-   -   -   The freeze dryer was back-filled with sterile filtered            nitrogen to a set point of 500 Torr (ca. 666 mbar or 66,600            Pascals), and the vials were fully closed using the            stoppers. The freeze dryer was then vented to atmospheric            pressure using sterile filtered air and the vials were            unloaded from the freeze dryer.        -   Each vial contained the freeze dried (lyophilised)            formulation as an off-white solid.

EXAMPLE 4 Preparation of (a) a Pharmaceutical Aqueous SolutionFormulation Comprising 22 mg/ml of1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea,ethanesulfonic acid and mannitol; and (b) a lyophilised CompositionThereof

-   -   (a) Ethanesulfonic acid (70% w/v) (3144.7 microL), was diluted        with water for irrigation (80 ml). Mannitol (2.8 g) was        dissolved in the buffer solution and stirred to achieve total        dissolution.        1-(4-{[4-(Dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea        (220 mg) was added to the solution and stirred until a        particle-free solution was achieved. Water for irrigation was        added with stirring to achieve target volume of 100 ml.        -   Samples of the formulation were analysed in accordance with            the methods of Example 1.    -   (b) The formulation from (a) was filled into 10 mL vials to a        target volume of 3 ml. The vials were partially stoppered (not        sealed) with a 20 mm Gray Lyo D777-1 V10-F597W FluroTec        Siliconised (trade mark) stopper. The vials were loaded into        stainless steel trays and inserted into a LSL1000 (trade mark)        freeze dryer. The shelf temperature was set at 5° C. The freeze        drying cycle was run using the tabulated method below.

Temper- Temperature ature change Rate/ (degrees Time (degrees C.)Condition Hold C.) (min.) per minute Pressure Loading Hold 5 n/a n/a 760Torr (1 Atmosphere) Stabilisation Hold 5 120 n/a 760 Torr (1 Atmosphere)Freeze Rate −40 480 0.1 deg. C./min 760 Torr (1 Atmosphere) Hold −40 180n/a 760 Torr (1 Atmosphere) Annealing Rate −12 280 0.1 deg. C./min 760Torr (1 Atmosphere) Hold −12 180 n/a 760 Torr (1 Atmosphere) CoolingRate −40 280 0.1 deg. C./min 760 Torr (1 Atmosphere) Evacuation Hold −40100 n/a 90 mTorr Primary Hold −40 30 n/a 90 mTorr Drying Rate −30 1000.5 deg. C./min 90 mTorr Hold −30 5450 n/a 90 mTorr Secondary Rate 20500 0.5 deg. C./min 90 mTorr Drying Hold 20 500 n/a 90 mTorr Rate 40 2000.5 deg. C./min 90 mTorr Hold 40 500 n/a 90 mTorr

-   -   -   The freeze dryer was back-filled with sterile filtered            nitrogen to a set point of 500 Torr (ca. 666 mbar or 66,600            Pascals), and the vials were fully closed using the            stoppers. The freeze dryer was then vented to atmospheric            pressure using sterile filtered air and the vials were            unloaded from the freeze dryer.        -   Each vial contained the freeze dried (lyophilised)            formulation as an off-white solid.

EXAMPLE 5A Reconstitution of a Pharmaceutical Aqueous SolutionFormulation Comprising 22 mg/ml of1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea,methanesulfonic acid and mannitol from a lyophilised Solid Composition

A vial of lyophilised solid composition prepared in Example 3(b) wasreconstituted as follows.

Water for irrigation (3 ml) was injected using a syringe into the vialcontaining the lyophilised composition prepared in Example 3(b). Themixture was swirled until a particle-free solution was obtained.

The reconstituted formulation was analysed in accordance with themethods of Example 1.

FIG. 2 shows OPM micrographs taken immediately after reconstitution at100× magnification. There was no evidence of any particulate orcrystalline material within the sample.

EXAMPLE 5B Reconstitution of a Pharmaceutical Aqueous SolutionFormulation Comprising 22 mg/ml of1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea,ethanesulfonic acid and mannitol from a lyophilised Solid Composition

A vial of lyophilised solid composition prepared in Example 4(b) wasreconstituted as follows.

Water for irrigation (3 ml) was injected using a syringe into the vialcontaining the lyophilised composition prepared in Example 4(b). Themixture was swirled until a particle-free solution was obtained.

The reconstituted formulation was analysed in accordance with themethods of Example 1.

FIG. 1 shows OPM micrographs taken immediately after reconstitution at100× magnification. There is no evidence of any particulate orcrystalline material within the sample. The opalescence of the solutionthat was observed is likely due to the presence of a chromonic liquidcrystal phase.

EXAMPLES 6-18

Examples 6-18 were prepared in accordance with the method of therelevant Example 1, 2, 3(a) or 4(a) using the ingredient specificationtabulated below.

Target API API Acid Acid mannitol volume Acid Example (mg/ml) (mg) (mM)(ml) (mg) (ml) MSA  1 22 2200 100 0.65 0 100  3(a) 22 2200 100 0.65 2800100  6 8 800 100 0.65 4200 100  7 10 1000 100 0.65 4000 100  8 13 1300100 0.65 3700 100  9 15 1500 100 0.65 3500 100 10 15 1500 100 0.65 0 10011 30 3000 100 0.65 2000 100 12 30 3000 100 0.65 0 100 13 40 4000 1000.65 1000 50 14 40 4000 100 0.65 0 50 15 20 2000 50 0.325 3000 50 ESA  222 2200 100 0.93 0 100  4(a) 22 2200 100 0.93 2800 100 16 30 3000 1000.93 2000 100 17 20 2000 50 0.46 3000 50 18 10 1000 100 0.93 4000 100MSA = methanesulphonic acid ESA = ethanesulphonic acid API =1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea

EXAMPLE 19 Preparation of a Pharmaceutical Aqueous Solution FormulationComprising 35 mg/ml of1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea,20% w/v 2-hydroxypropyl-beta-cyclodextrin and methanesulfonic acid

Methanesulfonic acid (99% w/w purity) (0.65 ml, 100 mM) was dissolved inwater for irrigation (80 ml). 2-Hydroxypropyl-beta-cyclodextrin (93% w/wadjusted potency) (21.57 g, 14.72 mM) was added and the solution wasstirred until a particle-free solution was achieved.1-(4-{[4-(Dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea(350 mg, 0.56 mM) was added to the solution and stirred until aparticle-free solution was achieved. Water for irrigation was added withstirring to achieve a target volume of 100 ml.

Samples of the formulation were analysed in accordance with the methodsof Example 1.

EXAMPLE 20 Preparation of a Pharmaceutical Aqueous Solution FormulationComprising 35 mg/ml of1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea,ethanesulfonic acid and 20% w/v 2-hydroxypropyl-beta-cyclodextrin

Ethanesulfonic acid (70% w/v) (3144.7 microL, 100 mM) was diluted withwater for irrigation (80 ml). 2-Hydroxypropyl-beta-cyclodextrin (93% w/wadjusted potency) (21.57 g, 14.72 mM) was added and the solution wasstirred until a particle-free solution was achieved.1-(4-{[4-(Dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea(350 mg, 0.56 mM) was added to the solution and stirred until aparticle-free solution was achieved. Water for irrigation was added withstirring to achieve target volume of 100 ml.

Samples of the formulation were analysed in accordance with the methodsof Example 1.

EXAMPLE 21 Preparation of a Pharmaceutical Aqueous Solution FormulationComprising 20 mg/ml of1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea,ethanesulfonic acid and 20% w/v gamma-cyclodextrin

Ethanesulfonic acid (70% w/v) (3144.7 microL, 100 mM) was diluted withwater for irrigation (80 ml). Gamma-cyclodextrin (assumed 100% potency)(20 g, 15.4 mM) was added and the solution was stirred until aparticle-free solution was achieved.1-(4-{[4-(Dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea(200 mg, 0.32 mM) was added to the solution and stirred until aparticle-free solution was achieved. Water for irrigation was added withstirring to achieve target volume of 100 ml.

Samples of the formulation were analysed in accordance with the methodsof Example 1.

EXAMPLE 22 Preparation of a Pharmaceutical Aqueous Solution FormulationComprising 30 mg/ml of1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea,methanesulfonic acid and 20% w/v sulphobutylether-3-cyclodextrin (SBECD)

Methanesulfonic acid (99% w/w purity) (0.65 ml, 100 mM) was dissolved inwater for irrigation (80 ml). Sulphobutylether-3-cyclodextrin (SBECD)(93% w/w adjusted potency) (21.57 g, 9.62 mM) was added and the solutionwas stirred until a particle free solution was achieved.1-(4-{[4-(Dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea(300 mg, 0.48 mM) was added to the solution and stirred until aparticle-free solution was achieved. Water for irrigation was added withstirring to achieve a target volume of 100 ml.

Samples of the formulation were analysed in accordance with the methodsof Example 1.

EXAMPLE 23 Preparation of a Pharmaceutical Aqueous Solution FormulationComprising 30 mg/ml of1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea,methanesulfonic acid and 20% w/v gamma-cyclodextrin

Methanesulfonic acid (99% w/w purity) (0.65 ml, 100 mM) was diluted withwater for irrigation (80 ml). Gamma-cyclodextrin (assumed 100% potency)(20 g, 15.42 mM) was added and the solution was stirred until aparticle-free solution was achieved.1-(4-{[4-(Dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea(300 mg, 0.48 mM) was added to the solution and stirred until aparticle-free solution was achieved. Water for irrigation was added withstirring to achieve target volume of 100 ml.

Samples of the formulation were analysed in accordance with the methodsof Example 1.

FURTHER EXAMPLES OF THE PREPARATION OF PHARMACEUTICAL AQUEOUS SOLUTIONFORMULATIONS COMPRISING1-(4-{[4-(DIMETHYLAMINO)PIPERIDIN-1-YL]CARBONYL}PHENYL)-3-[4-(4,6-DIMORPHOLIN-4-YL-1,3,5-TRIAZIN-2-YL)PHENYL]UREA,A BETA- OR GAMMA-CYCLODEXTRIN AND METHANESULFONIC OR ETHANESULFONIC ACID

The following, tabulated Examples (indicated by a tick “√” or cross “x”in the Table) (target volume=100 ml) were prepared in accordance withthe method of the relevant Example 19, 20, 21, 22, 23 using theingredient specification tabulated below.

These Examples were analysed by the visual method defined in EuropeanPharmacopoeia Method 2.9.20 and the OPM method both as described inExample 1. The results are also tabulated below.

In this Table “particle-free” means that the the formulation wasvisually clear and free of visible crystallites or particulates, and“opalescent” means that the the formulation had an opalescence that isthought to result from the formation of a chromonic liquid crystalphase.

API mg/ml/API mM 10/16.2 15/24.4 20/32.5 25/40.6 30/48.7 35/56.9 MSA 100HPBCD ✓ (1) ✓ (1) ✓ (1) ✓ (1) ✓ (1) ✓ (1) mM (20% W/V) (EXAM- PLE 19)MSA 100 AlphaCD  x (3)  x (3)  x (3)  x (3)  x (3)  x (3) mM (20% w/v)MSA 100 GammaCD ✓ (1) ✓ (1) ✓ (1) ✓ (1) ✓ (1)  x (2) mM (20% w/v) (EXAM-PLE 23) MSA 100 SBECD ✓ (1) ✓ (1) ✓ (1) ✓ (1) ✓ (1)  x (2) mM (20% w/v)(EXAM- PLE 22) MSA 100 HPBCD ✓ (1)  x (2) mM (20% w/v) MSA 100 HPBCD ✓(1) ✓ (1) mM (25% w/v) ESA 100 SBECD ✓ (1) ✓ (1) ✓ (1) ✓ (1) ✓ (1) ✓ (1)mM (20% w/v) ESA 100 HPBCD ✓ (1) mM (20% w/v) (EXAM- PLE 20) ESA 100Gamma CD ✓ (1)  x (2)  x (2)  x (2) mM (20% w/v) (EXAM- PLE 21) APImg/ml/API mM 40/65.0 45/73.1 50/81.2 55/89.3 60/97.5 65/105.6 MSA 100HPBCD ✓ (1)  ✓ (1) ✓ (1) x (2) mM (20% W/V) MSA 100 AlphaCD x (3)  x (3) x (3) x (3) x (3) mM (20% w/v) MSA 100 GammaCD mM (20% w/v) MSA 100SBECD x (2) mM (20% w/v) MSA 100 HPBCD x (2) x (3) x (3) x (3) mM (20%w/v) MSA 100 HPBCD x (2) x (3) x (3) x (3) mM (25% w/v) ESA 100 SBECD x(2) mM (20% w/v) ESA 100 HPBCD x (2) mM (20% w/v) ESA 100 Gamma CD mM(20% w/v) Key MSA = methanesulphonic acid ESA = ethanesulphonic acid API=1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea HPBCD =2-hydroxypropyl-beta-cyclodextrin AlphaCD = alpha-cyclodextrin SBECD =sulphobutylether-β-cyclodextrin GammaCD = gamma-cyclodextrin (1) =particle-free (and non-opalescent). All these Examples studied are freeof visible crystallite or particulate matter and meet the required“clear solution” definition as described earlier. (2) = particulate,opalescent (3) = particulate suspension

EXAMPLE 24 Preparation of (a) a Pharmaceutical Aqueous SolutionFormulation Comprising 20 mg/ml of1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea,methanesulfonic acid and 20% w/v 2-hydroxypropyl-beta-cyclodextrin; and(b) a lyophilised Composition Thereof

(a) Methanesulfonic acid (99% w/w purity) (0.336 ml) (35 mM) wasdissolved in water for irrigation (80 ml).2-Hydroxypropyl-beta-cyclodextrin (21.57 g, 14.72 mM) was dissolved inthis buffer solution by stirring to achieve total dissolution.1-(4-{[4-(Dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea(200 mg, 0.325 mM) was added to the solution and stirred until aparticle-free solution was achieved. Water for irrigation was added withstirring to achieve a target volume of 100 ml.(b) The formulation from (a) was filled into 10 mL vials to a targetvolume of 3 ml. The vials were partially stoppered (not sealed) with a20 mm Gray Lyo D777-1 V10-F597W FluroTec Siliconised (trade mark)stopper. The vials were loaded into stainless steel trays and insertedinto a LSL1000 (trade mark) freeze dryer. The shelf temperature was setat 25° C. The freeze drying cycle was run using the tabulated methodbelow.

Temperature Rate/ Temperature Time change Pressure Condition Hold (° C.)(Minutes) (° C./minute) (mbar) Loading Hold 25 n/a n/a 1 Atmosphere*Stabilisation Hold 25 120 n/a 1 Atmosphere* Freeze Rate −25 500 0.1 1Atmosphere* Hold −25 180 n/a 1 Atmosphere* Rate −40 150 0.1 1Atmosphere* Hold −40 150 n/a 1 Atmosphere* Evacuation Hold −40 n/a n/a75 mTorr Primary Rate −15 112 0.5 75 mTorr Drying Hold −15 5810  n/a 75mTorr Secondary Rate 0 150 0.1 75 mTorr Drying Hold 0 480 n/a 75 mTorrRate 40 400 0.1 75 mTorr Hold 40 480 n/a 75 mTorr Rate 25 150 0.1 75mTorr Stoppering Hold 25 n/a n/a 500 Torr Storage Hold 25 n/a n/a (*760Torr)

The freeze dryer was back-filled with sterile filtered nitrogen to a setpoint of 500 Torr (ca. 666 mbar or 66,600 Pascals), and the vials werefully closed using the stoppers. The freeze dryer was then vented toatmospheric pressure using sterile filtered air and the vials wereunloaded from the freeze dryer.

Each vial contained the freeze dried (lyophilised) formulation as anoff-white solid.

ANALYSIS OF EXAMPLES 1-18

The Examples shown in the following Table were analysed by the visualmethod defined in European Pharmacopoeia Method 2.9.20 and the OPMmethod both as described in Example 1. The results are tabulated below.

Further, the formulations of Examples 1, 2 and 6-18 were eachlyophilised by the same method used in Examples 3(b) and 4(b) and theneach reconstituted by the same method as used in Examples 5A and 5B.

In this Table “particle-free” means that the the formulation wasvisually clear and free of visible crystallites or particulates, and“opalescent, particle-free” means that the the formulation was free ofvisible crystallites or particulates but had a solution opalescence thatis thought to result from the formation of a chromonic liquid crystalphase. There are Examples shown where the opalescence disappears onreconstitution of the formulation following lyophilisation. All Examplesstudied are free of visible crystallite or particulate matter and meetthe required “clear solution” definition as described earlier.

Analysis for formulation Analysis for obtained after formulationreconstitution API API Acid mannitol prepared in following Acid Example(mg/ml) (mg) (mM) (mg) Example lyophilisation MSA  1 22 2200 100 0opalescent, particle-free particle-free  3(a) 22 2200 100 2800opalescent, — particle-free  5A — particle-free  6 8 800 100 4200particle-free particle-free  7 10 1000 100 4000 particle-freeparticle-free  8 13 1300 100 3700 opalescent, particle-freeparticle-free  9 15 1500 100 3500 opalescent, particle-freeparticle-free 10 15 1500 100 0 opalescent, particle-free particle-free11 30 3000 100 2000 opalescent, particle-free particle-free 12 30 3000100 0 opalescent, opalescent, particle-free particle-free 13¹ 40 4000100 1000 opalescent, opalescent, particle-free particle-free 14¹ 40 4000100 0 opalescent, opalescent, particle-free particle-free 15 20 2000 503000 opalescent, opalescent, particle-free particle-free ESA  2 22 2200100 0 opalescent, opalescent, particle-free particle-free  4(a) 22 2200100 2800 opalescent, — particle-free  5B — opalescent, particle-free 1630 3000 100 2000 opalescent, opalescent, particle-free particle-free 1720 2000 50 3000 opalescent, particle-free particle-free 18 10 1000 1004000 particle-free particle-free Footnote ¹Although this formulationmeets the “clear solution” criterion, it is unsuitable for the intendedpurpose since it is a viscous solution that reconstitutes very slowlyKey MSA = methanesulphonic acid ESA = ethanesulphonic acid API =1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea

Chemical Stability of a Lyophilised Solid Formulations of the Invention

Two Samples of lyophilised formulations of the invention were prepared.

-   -   Sample A was prepared by a similar procedure to that of Example        3 except that 2000 mg of        1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea        (i.e. 20 mg/ml), 100 mM of methanesulfonic acid (0.65 ml) and        3000 mg of mannitol were used to prepare the lyophile.    -   Sample B was prepared by a similar procedure to that of Example        4 except that 2000 mg of        1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea        (i.e. 20 mg/ml), 100 mM of ethanesulfonic acid and 3000 mg of        mannitol were used to prepare the lyophile.

Separate portions of Samples A and B were each housed in 10 mL clearvials and 20 were stored at 25° C./60% Relative Humidity (“RH”), 40°C./75% RH or 5° C. for 6 weeks.

After 6 weeks storage as above, the Samples were each tested forchemical purity using Ultra High Performance Liquid Chromatography(UHPLC) using the following methodology in order to measure any chemicaldegradation during the period of testing.

UHPLC Method

The solutions, samples, standards and UHPLC method are as below:

Reference Standard:1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]ureawith a known potency value.

Diluent: Acetonitrile/Water/Trifluoroacetic acid (750:250:1 v/v/v)

Mobile Phase A: Acetonitrile/Water/Trifluoroacetic acid (97:3:1 v/v/v)

Mobile Phase B: Acetonitrile/Trifluoroacetic acid (1000:1 v/v).

(Note: larger or smaller volumes of solutions may be prepared using theappropriate ratio of components)

Standard and Check Standard Preparations:

-   -   Accurately prepare two solutions of ca. 0.2 mg/mL (+/−10%) of        1-(4-{[4-(dimethylamino)        piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea        Reference Standard in Diluent, and record the concentrations        accurately of both. These are the Standard and Check standard        preparations.        Sensitivity Solution:    -   Accurately dilute the Standard preparation to a concentration of        approximately 0.1 microgram/ml of        1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea        using the Diluent.        Sample Preparation:    -   Reconstitute Sample A or B after storage by adding 3.0 ml of        water to each in the 10 ml vial, shake the vial to dissolve the        solid and wait for the bubbles to disappear. Transfer 1.0 ml of        the solution into a 100 ml volumetric flask. Dilute to the set        volume with Diluent.        Chromatographic Conditions:    -   Liquid chromatographic system—Agilent 1290 Infinity II™ with 380        μl Jet Weaver™    -   Column: Waters BEH C18™ 15 cm×2.1 mm, 1.7 μm or equivalent    -   Column Temperature: 20° C.    -   Injection Volume: 2 μL    -   Flow Rate: 0.25 mL/min.    -   Flow Cell: G4212-60008, 10 mm path length, 1.0 μL    -   Detection: UV at 240 nm/4 nm slit width    -   Run Time: 77 minutes    -   Mobile Phase A    -   Mobile Phase B    -   Needle wash solution: Water/Acetonitrile (95:5 v/v), multi wash        20 s.    -   Seal wash solution: Water/Propan-2-ol (90:10 v/v)        Linear Gradient Table:

Time (minutes) % Mobile Phase A % Mobile Phase B 0 95 5 5.0 95 5 31.4 7822 42.3 78 22 65.0 5 95 67.0 5 95 67.1 95 5 77.0 95 5Explanatory Notes

Condition the UHPLC system, prior to starting the analysis, with themobile phases. Prior to running samples, ensure that the system issuitable for use by injecting blank diluent, sensitivity solution andstandard preparation using the chromatographic conditions above.

The following criteria must be satisfied on initial UHPLC set-up orafter any significant change to the system. It is recommended to injectat least one conditioning blank prior to testing system suitability.

# of Test Injections Solution Criteria Blank 1 Diluent Chromatogramsimilar to FIGS. 3 and 4 Signal to 1 Sensitivity European Pharmacopoeia(EP)/United Noise Solution States Pharmacopoeia (USP) Signal to Noise ≥10 Repeatability 5 Standard Relative Standard Deviation ≤ 2.0% Retentiontime  1* preparation 38-44 minutes Efficiency Plate number for 1-(4-{[4-(Plate)** (dimethylamino)piperidin-1- yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2- yl)phenyl]urea peak ≥ 10,000 Peak 0.9≤ T ≤ 2.0 for 1-(4-{[4- Asymmetry (dimethylamino)piperidin-1- (T)**yl]carbonyl}phenyl)-3-[4-(4,6- dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea peak Resolution 1 Resolution between 1-(4-{[4-(dimethylamino)piperidin-1- yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2- yl)phenyl]urea peak and ((4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)- l2-azaneyl)((4-(4-(methyl-l2-azaneyl)piperidine-1-carbonyl)phenyl)-l2- azaneyl)methanone ≥ 1.0 *Useaverage of all system suitability (repeatability) injections. **Refer toUnited States Pharmacopoeia (USP) calculation equations for Efficiencyand Peak Asymmetry.

Inject the check standard preparation according to the chromatographicconditions above. The response factor (calculated from the area,standard weight, dilution factor and purity factor of the standard) ofthis check standard preparation must be within ±2% of the standardpreparation.

After the system suitability has been demonstrated, inject the blanksolution, standard preparation and prepared test samples, followed by aninjection of the standard preparation, according to the chromatographicconditions above. It is recommended that no more than 6 test samples beinjected between standard preparation injections. For each injection(standard and sample), measure the retention time and area of the1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]ureapeak in each chromatogram. For each sample injection, also measure theretention times and peak area of any peaks present in the sampleinjection that do not appear in the blank injection. Do not integrategradient artifacts, if present. Compare the blank injection chromatogramto the sample chromatogram to determine which peaks in the sample arerelated to the blank and gradient artifact peaks. Calculate the % w/wdegradants and report the individual degradant peaks which are at orabove 0.05% w/w. Unknown degradants should be reported individually bytheir relative retention time. Known degradants should be reportedindividually by name.

The results are summarised in the Tables below.

Key

-   -   NMT=Not More Than.    -   RRT=Relative Retention Time    -   NO=Not Observed        Degradant 1

Degradants 2, 3, 4, 5 and 6

These were each characterised by their RRT only.

Sample A Results

5° C. 25° C./60% RH 40° C./75% RH Degradant 1 0.10 0.10 0.10 Degradant 2NMT 0.05 NO NO RRT~1.150 Degradant 3 NMT 0.05 NMT 0.05 NMT 0.05RRT-1.179 Degradant 5 0.14 0.25 0.65 RRT~1.24 Degradant 6 0.08 0.08 0.08RRT~1.324 Total 0.32 0.43 0.83 degradants (w/w)Sample B Results

5° C. 25° C./60% RH 40° C./75% RH Degradant 1 0.09 0.12 0.11 Degradant 2NO 0.06 NO RRT~1.150 Degradant 3 0.06 0.07 NMT 0.05 RRT~1.179 Degradant4 NO NO NO RRT~1.185 Degradant 5 0.14 0.25 0.99 RRT~1.24 Degradant 60.08 0.08 0.08 RRT~1.324 Total 0.37 0.58 1.18 degradants (w/w)

CONCLUSION

The results show that Samples A and B are chemically stable for at least6 weeks at 25° C./60% RH.

The invention claimed is:
 1. A pharmaceutical aqueous solutionformulation comprising (a)1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea,or a methanesulphonate salt thereof, methanesulphonic acid and water,wherein1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]ureais present at a solution concentration of less than 35 mg/ml or up to 30mg/ml and sufficient methanesulphonic acid is present to provide a clearsolution; or (b)1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea,or an ethanesulphonate salt thereof, ethanesulphonic acid and water,wherein1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]ureais present at a solution concentration of less than 35 mg/ml or up to 30mg/ml and sufficient ethanesulphonic acid is present to provide a clearsolution.
 2. A pharmaceutical aqueous solution formulation as claimed inclaim 1 comprising (a)1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea,or a methanesulphonate salt thereof, methanesulphonic acid and water,wherein1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]ureais present at a solution concentration of from 6 to 30 mg/ml andsufficient methanesulphonic acid is present to provide a clear solution;or (b)1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea,or an ethanesulphonate salt thereof, ethanesulphonic acid and water,wherein1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]ureais present at a solution concentration of from 6 to 30 mg/ml andsufficient ethanesulphonic acid is present to provide a clear solution.3. A pharmaceutical aqueous solution formulation as claimed in claim 2comprising1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea,methanesulphonic acid and water, wherein1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]ureais present at a solution concentration of from 6 to 22 mg/ml andsufficient methanesulphonic acid is present to provide a clear solution.4. A pharmaceutical aqueous solution formulation as claimed in claim 2comprising1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]ureamethanesulphonate, methanesulphonic acid and water, wherein1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]ureais present at a solution concentration of from 6 to 22 mg/ml andsufficient methanesulphonic acid is present to provide a clear solution.5. A pharmaceutical aqueous solution formulation as claimed in claim 2comprising1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea,ethanesulphonic acid and water, wherein1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]ureais present at a solution concentration of from 6 to 22 mg/ml andsufficient ethanesulphonic acid is present to provide a clear solution.6. A pharmaceutical aqueous solution formulation as claimed in claim 2comprising1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]ureaethanesulphonate, ethanesulphonic acid and water, wherein1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]ureais present at a solution concentration of from 6 to 22 mg/ml andsufficient ethanesulphonic acid is present to provide a clear solution.7. A pharmaceutical aqueous solution formulation as claimed in claim 1that additionally comprises a pharmaceutically acceptablebeta-cyclodextrin or gamma-cyclodextrin.
 8. A pharmaceutical aqueoussolution formulation as claimed in claim 7 wherein the pharmaceuticallyacceptable beta-cyclodextrin is hydroxypropyl-beta-cyclodextrin orsulphobutylether-β-cyclodextrin (SBECD), or is a mixture thereof, andthe pharmaceutically acceptable gamma-cyclodextrin isgamma-cyclodextrin.
 9. A pharmaceutical aqueous solution formulationcomprising1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]ureaor1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]ureamethanesulphonate, methanesulphonic acid,2-hydroxypropyl-beta-cyclodextrin and water, wherein1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]ureaor1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]ureamethanesulphonate is present at a solution concentration of less than 55mg/ml or up to 50 mg/ml and sufficient methanesulphonic acid and2-hydroxypropyl-beta-cyclodextrin are present to provide a clearsolution.
 10. A pharmaceutical aqueous solution formulation as claimedin claim 9, wherein1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]ureaor1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]ureamethanesulphonate is present at a solution concentration of up to 45mg/ml, up to 40 mg/ml, up to 35 mg/ml, up to 30 mg/ml, from 6 to 50mg/ml, from 6 to 30 mg/ml, from 8 to 30 mg/ml, from 10 to 35 mg/ml, from10 to 30 mg/ml, from 8 to 22 mg/ml, from 10 to 22 mg/ml, from 15 to 22mg/ml, from 10 to 20 mg/ml, from 6 to 25 mg/ml or from 10 to 25 mg/mland sufficient methanesulphonic acid and2-hydroxypropyl-beta-cyclodextrin are present to provide a clearsolution.
 11. A pharmaceutical aqueous solution formulation comprising1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]ureaor1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]ureamethanesulphonate, methanesulphonic acid,sulphobutylether-β-cyclodextrin and water, wherein1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]ureaor1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]ureamethanesulphonate is present at a solution concentration of less than 35mg/ml or up to 30 mg/ml and sufficient methanesulphonic acid andsulphobutylether-β-cyclodextrin are present to provide a clear solution.12. A pharmaceutical aqueous solution formulation as claimed in claim11, wherein1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]ureaor1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]ureamethanesulphonate is present at a solution concentration of from 6 to 30mg/ml, from 8 to 30 mg/ml, from 10 to 30 mg/ml, from 8 to 22 mg/ml, from10 to 22 mg/ml, from 15 to 22 mg/ml, from 10 to 20 mg/ml, from 6 to 25mg/ml or from 10 to 25 mg/ml and sufficient methanesulphonic acid andsulphobutylether-β-cyclodextrin are present to provide a clear solution.13. A pharmaceutical aqueous solution formulation comprising1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]ureaor1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]ureamethanesulphonate, methanesulphonic acid, gamma-cyclodextrin and water,wherein1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]ureaor1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]ureamethanesulphonate is present at a solution concentration of less than 35mg/ml or up to 30 mg/ml and sufficient methanesulphonic acid andgamma-cyclodextrin are present to provide a clear solution.
 14. Apharmaceutical aqueous solution formulation as claimed in claim 13,wherein1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]ureaor1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]ureamethanesulphonate is present at a solution concentration of from from 6to 30 mg/ml, from 8 to 30 mg/ml, from 10 to 30 mg/ml, from 8 to 22mg/ml, from 10 to 22 mg/ml, from 15 to 22 mg/ml, from 10 to 20 mg/ml,from 6 to 25 mg/ml or from 10 to 25 mg/ml and sufficientmethanesulphonic acid and gamma-cyclodextrin are present to provide aclear solution.
 15. A pharmaceutical aqueous solution formulationcomprising1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]ureaor1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]ureaethanesulphonate, ethanesulphonic acid,2-hydroxypropyl-beta-cyclodextrin and water, wherein1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]ureaor1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]ureaethanesulphonate is present at a solution concentration of less than 40mg/ml or up to 35 mg/ml and sufficient ethanesulphonic acid and2-hydroxypropyl-beta-cyclodextrin are present to provide a clearsolution.
 16. A pharmaceutical aqueous solution formulation as claimedin claim 15, wherein1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]ureaor1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]ureaethanesulphonate is present at a solution concentration of up to 30mg/ml, from 6 to 30 mg/ml, from 8 to 30 mg/ml, from 10 to 35 mg/ml, from10 to 30 mg/ml, from 8 to 22 mg/ml, from 10 to 22 mg/ml, from 15 to 22mg/ml, from 10 to 20 mg/ml, from 6 to 25 mg/ml or from 10 to 25 mg/mland sufficient ethanesulphonic acid and2-hydroxypropyl-beta-cyclodextrin are present to provide a clearsolution.
 17. A pharmaceutical aqueous solution formulation comprising1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]ureaor1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]ureaethanesulphonate, ethanesulphonic acid, sulphobutylether-β-cyclodextrinand water, wherein1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]ureaor1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]ureaethanesulphonate is present at a solution concentration of less than 40mg/ml or up to 35 mg/ml and sufficient ethanesulphonic acid andsulphobutylether-β-cyclodextrin are present to provide a clear solution.18. A pharmaceutical aqueous solution formulation as claimed in claim17, wherein1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]ureaor1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]ureaethanesulphonate is present at a solution concentration of up to 30mg/ml, from 6 to 30 mg/ml, from 8 to 30 mg/ml, from 10 to 30 mg/ml, from8 to 22 mg/ml, from 10 to 22 mg/ml, from 15 to 22 mg/ml, from 10 to 20mg/ml, from 6 to 25 mg/ml or from 10 to 25 mg/ml and sufficientethanesulphonic acid and sulphobutylether-β-cyclodextrin are present toprovide a clear solution.
 19. A pharmaceutical aqueous solutionformulation comprising1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]ureaor1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]ureaethanesulphonate, ethanesulphonic acid, gamma-cyclodextrin and water,wherein1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]ureaor1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]ureaethanesulphonate is present at a solution concentration of less than 25mg/ml or up to 20 mg/ml and sufficient ethanesulphonic acid andgamma-cyclodextrin are present to provide a clear solution.
 20. Apharmaceutical aqueous solution formulation as claimed in claim 19,wherein1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]ureaor1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]ureaethanesulphonate is present at a solution concentration of from 6 to 20mg/ml, from 8 to 20 mg/ml, from 10 to 20 mg/ml, from 8 to 15 mg/ml, orfrom 15 to 20 mg/ml and sufficient ethanesulphonic acid andgamma-cyclodextrin are present to provide a clear solution.
 21. Aformulation as claimed in claim 1, wherein from 10 to 200 mM, 20 to 200mM, 30 to 200 mM or from 50 to 200 mM of methanesulphonic acid orethanesulphonic acid, as appropriate, is used.
 22. A formulation asclaimed in claim 7, wherein from 2 to 30% w/v, 3 to 20% w/v, from 5 to20% w/v or from 15 to 30% w/v of the cyclodextrin is used.
 23. Alyophilized formulation obtainable by freeze drying a formulation asclaimed in claim
 1. 24. A lyophilized formulation as claimed in claim 23comprising mannitol as a bulking agent.
 25. A pharmaceutical aqueoussolution formulation obtainable as a clear solution by reconstitution orconstitution of a lyophilized formulation as claimed in claim 23 usingwater or an aqueous solution comprising a tonicity modifier.
 26. Apharmaceutical aqueous solution formulation as claimed in claim 25wherein the tonicity modifier is dextrose, sucrose or mannitol, or is amixture of any 2 or more thereof.
 27. A pharmaceutical aqueous solutionformulation as claimed in claim 1, that is adjusted, as necessary, tohave a pH suitable for intravenous or parenteral administration.
 28. Aformulation as claimed in claim 1 for use as a medicament.
 29. Aformulation as claimed in claim 1 for use in the treatment of breastcancer, ovarian cancer, endometrial cancer, colorectal cancer, renalcancer, glioblastoma, lung cancer or prostate cancer.
 30. A method oftreatment of cancer in a mammal comprising treatment of the mammal withan effective amount of a formulation as claimed in claim 1, wherein thecancer is breast cancer, ovarian cancer, endometrial cancer, colorectalcancer, renal cancer, glioblastoma, lung cancer or prostate cancer.